The Landscape of Amyloid-Targeting Therapeutics in Alzheimer's Disease Part 1: Anti-Amyloid Approaches

Abstract The amyloid cascade hypothesis has guided Alzheimer's disease (AD) pharmacotherapy for three decades, yielding its first regulatory successes in recent years. This review summarises the mechanisms, clinical efficacy, and safety profiles of six anti-amyloid agents at different stages of development. Lecanemab, a humanized IgG1 antibody targeting soluble Aβ protofibrils, demonstrated a 27% slowing of clinical decline on the CDR-SB in the CLARITY-AD Phase 3 trial and received full FDA and conditional EMA approval. Donanemab, directed against pyroglutamate-modified deposited amyloid (pGlu-Aβ), reduced disease progression by approximately 35% in participants with low/medium tau burden in TRAILBLAZER-ALZ 2 and was approved by both agencies in 2024. Aducanumab, targeting fibrillar Aβ, produced discordant results across the twin EMERGE and ENGAGE Phase 3 studies and was voluntarily withdrawn from the market in 2024. Solanezumab, binding monomeric soluble Aβ, failed to slow cognitive decline in the A4 preclinical trial. Remternetug, a second-generation anti-pGlu-Aβ antibody capable of achieving below-threshold amyloid clearance within three months, is currently being evaluated in ongoing Phase 3 trials. Valiltramiprosate (ALZ-801), an oral small-molecule Aβ aggregation inhibitor, met its primary endpoint exclusively in the pre-specified MCI subgroup of the APOLLOE4 trial, producing a 52% slowing of cognitive decline without ARIA risk. Across all agents, early intervention in biomarker-confirmed, tau-low populations consistently yields the greatest clinical benefit.